In the United States, 1.4 million people each year suffer a traumatic brain injury. Of those who survive, 80-90,000 people per year experience long-term disabilities, often including retrograde amnesia and deficits in learning and memory due to hippocampal neuronal cell loss. Bilateral loss of hippocampal neurons has been observed in 85% of fatal human head injury cases. Within the hippocampus, pyramidal neurons are particularly vulnerable to brain injury in humans as well as experimental animal models of TBI. Although the cognitive problems are among the most long-lasting and debilitating outcomes in patients, no neuroprotective therapy is available for this type of damage in human patients. Therefore, the need for the development of therapeutic strategies aiming at protecting these cells is critical. In the previous grant cycle, we identified a mammalian neurotrophin (NT4/5) that is neuroprotective for pyramidal neurons. A related neurotrophin, brain-derived neurotrophic factor (BDNF) was ineffective. The purpose of this proposal is to evaluate in detail the efficacy and mechanism of NT4/5-mediated hippocampal neuroprotection. Our proposed experiments will determine the functional benefit of this new theraputic molecule as well as the limitations associated with its use. Our Central Hypothesis is: NT4/5 rescue of CAS pyramidal neurons after TBI improves hippocampal function via upregulation of a specific set of neuroprotective genes. We will investigate this hypothesis by: (1) Determining whether NT4/5 treatment improves hippocampal function after experimental traumatic brain injury; (2) Determining the mechanism of NT4/5-mediated neuroprotection by examining 11 candidate genes upregulated by NT4/5 but not by BDNF; and (3) Determining the critical parameters for NT4/5 rescue of hippocampal neurons. We will use multiple levels of analysis (molecular, cellular, circuit and behavioral) to gain a detailed understanding of the mechanism of NT4/5 neuroprotection. These findings will provide insight for developing more specific therapies to ameliorate memory loss in TBI patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS040978-07
Application #
7341671
Study Section
Special Emphasis Panel (ZRG1-BINP-L (01))
Program Officer
Hicks, Ramona R
Project Start
2000-12-01
Project End
2011-12-31
Budget Start
2008-01-01
Budget End
2008-12-31
Support Year
7
Fiscal Year
2008
Total Cost
$345,652
Indirect Cost
Name
University of Pennsylvania
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Malik, Saafan Z; Maronski, Margaret A; Dichter, Marc A et al. (2012) The use of specific AAV serotypes to stably transduce primary CNS neuron cultures. Methods Mol Biol 846:305-19
Malik, Saafan Z; Motamedi, Shahab; Royo, Nicolas C et al. (2011) Identification of potentially neuroprotective genes upregulated by neurotrophin treatment of CA3 neurons in the injured brain. J Neurotrauma 28:415-30
Hånell, Anders; Clausen, Fredrik; Björk, Maria et al. (2010) Genetic deletion and pharmacological inhibition of Nogo-66 receptor impairs cognitive outcome after traumatic brain injury in mice. J Neurotrauma 27:1297-309
Ortinski, Pavel I; Dong, Jinghui; Mungenast, Alison et al. (2010) Selective induction of astrocytic gliosis generates deficits in neuronal inhibition. Nat Neurosci 13:584-91
Marklund, N; Morales, D; Clausen, F et al. (2009) Functional outcome is impaired following traumatic brain injury in aging Nogo-A/B-deficient mice. Neuroscience 163:540-51
Royo, Nicolas C; Vandenberghe, Luk H; Ma, Jing-Yuan et al. (2008) Specific AAV serotypes stably transduce primary hippocampal and cortical cultures with high efficiency and low toxicity. Brain Res 1190:15-22
Conte, Valeria; Raghupathi, Ramesh; Watson, Deborah J et al. (2008) TrkB gene transfer does not alter hippocampal neuronal loss and cognitive deficits following traumatic brain injury in mice. Restor Neurol Neurosci 26:45-56
Marklund, Niklas; Bareyre, Florence M; Royo, Nicolas C et al. (2007) Cognitive outcome following brain injury and treatment with an inhibitor of Nogo-A in association with an attenuated downregulation of hippocampal growth-associated protein-43 expression. J Neurosurg 107:844-53
Royo, N C; LeBold, D; Magge, S N et al. (2007) Neurotrophin-mediated neuroprotection of hippocampal neurons following traumatic brain injury is not associated with acute recovery of hippocampal function. Neuroscience 148:359-70
Chen, H Isaac; Bakshi, Asha; Royo, Nicolas C et al. (2007) Neural stem cells as biological minipumps: a faster route to cell therapy for the CNS? Curr Stem Cell Res Ther 2:13-22

Showing the most recent 10 out of 50 publications